ABSTRACT Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health.
The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed.
Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms.
Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited.
There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively.

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Background
Historically, the focus of Non Communicable Disease (NCD) prevention and control has been cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer and chronic respiratory diseases. Collectively, these account for more deaths than any other NCDs. Despite recent calls to include the common mental disorders (CMDs) of depression and anxiety under the NCD umbrella, prevention and control of these CMDs remain largely separate and independent.DiscussionIn order to address this gap, we apply a framework recently proposed by the Centers for Disease Control with three overarching objectives: (1) to obtain better scientific information through surveillance, epidemiology, and prevention research; (2) to disseminate this information to appropriate audiences through communication and education; and (3) to translate this information into action through programs, policies, and systems. We conclude that a shared framework of this type is warranted, but also identify opportunities within each objective to advance this agenda and consider the potential benefits of this approach that may exist beyond the health care system.

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Regular physical exercise/activity has been shown repeatedly to promote positive benefits in cognitive, emotional and motor domains concomitant with reductions in distress and negative affect. It exerts a preventative role in anxiety and depressive states and facilitates psychological well-being in both adolescents and adults. Not least, several meta-analyses attest to improvements brought about by exercise. In the present treatise, the beneficial effects of exercise upon cognitive, executive function and working memory, emotional, self-esteem and depressed mood, motivational, anhedonia and psychomotor retardation, and somatic/physical, sleep disturbances and chronic aches and pains, categories of depression are discussed. Concurrently, the amelioration of several biomarkers associated with depressive states: hypothalamic-pituitary-adrenal (HPA) axis homeostasis, anti-neurodegenerative effects, monoamine metabolism regulation and neuroimmune functioning. The notion that physical exercise may function as "scaffolding" that buttresses available network circuits, anti-inflammatory defences and neuroreparative processes, e.g. brain-derived neurotrophic factor (BDNF), holds a certain appeal.

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Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology.

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Research reportAssociation of exercise with quality of life and mood symptomsin a comparative effectiveness study of bipolar disorderLouisa G. Sylviaa,n, Edward S. Friedmanb, James H. Kocsisc, Emily E. Bernsteina,Benjamin D. Brodyc, Gustavo Kinrysa, David E. Kempd, Richard C. Sheltone,Susan L. McElroyf, William V. Bobog, Masoud Kamalih, Melvin G. McInnish,Mauricio Toheni, Charles L. Bowdenj, Terence A. Ketterk, Thilo Deckersbacha,Joseph R. Calabresed, Michael E. Thasel, Noreen A. Reilly-Harringtona, Vivek Singhj,Dustin J. Rabideaua, Andrew A. NierenbergaaThe Massachusetts General Hospital, USAbUniversity of Pittsburgh Medical Center, USAcWeill Cornell Medical College of Cornell University, USAdCase Western Reserve University, USAeUniversity of Alabama at Birmingham, USAfLindner Center for Hope, University of Cincinnati, USAgMayo Clinic, USAhUniversity of Michigan, USAiUniversity of New Mexico, USAjUniversity of Texas Health Science Center at San Antonio, USAkStanford University School of Medicine, USAlPerelman School of Medicine at the University of Pennsylvania, USAa r t i c l e i n f oArticle history:Received 24 June 2013Accepted 31 July 2013Available online 16 August 2013Keywords:Bipolar disorderMood symptomsExerciseQuality of lifeFunctioninga b s t r a c tBackground: Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course ofillness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency couldlead to interventions with powerful consequences on the course of illness and overall health.Methods: The present study examines baseline reports of exercise frequency of bipolar patients in a multi-sitecomparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic moodstabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed.Results: Approximately 40% of participants reported not exercising regularly (at least once per week). Lessfrequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms,and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencingmore mania in the past year and more current manic symptoms.Limitations: Exercise frequency was measured by self-report and details of the exercise were not collected.Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validitycannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that thegeneralizability of the findings could be limited.Conclusion: There appears to be a mood-specific relationship between exercise frequency and polarity suchthat depression is associated with less exercise and mania with more exercise in individuals with bipolardisorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients withdepressive or mood elevation symptoms, respectively.& 2013 Elsevier B.V. All rights reserved.1. IntroductionBipolar disorder is a severe, chronic, recurrent mental illnesscharacterized by depressive and manic/hypomanic mood episodesthat are associated with deficits in quality of life and psychosocialfunctioning (Coryell et al., 1993; Salvatore et al., 2007; Sanchez-Moreno et al., 2009; Tohen et al., 1990; Young and Grunze, 2013).Pharmacotherapy is associated with the persistence of symptoms inContents lists available at ScienceDirectjournal homepage: www.elsevier.com/locate/jadJournal of Affective Disorders0165-0327/$-see front matter & 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.jad.2013.07.031nCorrespondence to: Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford Street, Suite 580, Boston, MA 02138, USA.Tel.: þ617 643 4804; fax: þ617 726 6768.E-mail address: lsylvia2@partners.org (L.G. Sylvia).Journal of Affective Disorders 151 (2013) 722–727

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54–68% of the patients (Culver et al., 2007; Keitner et al., 1996) andis burdened by significant side effects, such as contributing to one′srisk of cardiovascular disease (De Almeida et al., 2012; Ketter, 2010;Serretti et al., 2013). This is particularly concerning as individualswith bipolar disorder are already at a higher risk for cardiovasculardisease (Khot et al., 2003; Krishnan, 2005; McIntyre et al., 2005;Soreca et al., 2008) compared to the general population, which leadsto comparatively higher rates of morbidity and mortality (Angstet al., 2002; Hennekens, 2007; Osby et al., 2001). Thus, there is aneed to not only improve the treatment of bipolar symptoms butalso to reduce their disproportionate medical burden.Regular physical activity is associated with lower risk for pre-mature mortality and improves risk factors for cardiovascular disease(Church et al., 2007; Cornelissen and Fagard, 2005). Evidence alsosuggests that exercise may improve course of bipolar illness and lifefunctioning (Sylvia et al., 2011; Ng et al., 2007). In other psychiatricand non-psychiatric populations, better exercise habits have beenassociated with lower levels of depression (De Moor et al., 2006;Mead et al., 2008; Otto et al., 2007; Palomo et al., 2008; Trivedi et al.,2011; Tsang et al., 2008), less stress (Vancamfort et al., 2011), lessneuroticism (De Moor et al., 2006), better sleep quality (Palomo et al.,2008), social contact (Carless and Douglas, 2008; Wright et al., 2012),energy (Crone and Guy, 2008), and better overall mental health(Crone and Guy, 2008; Ellis et al., 2007; Stathopoulou et al., 2006;Tordeurs et al., 2011; Vancamfort et al., 2011). Positive effects ofphysical activity for major depression have proven particularly robust(Harris et al., 2006; Tordeurs et al., 2011), for example associatingwith higher remission rates (Blumenthal et al., 2007; Trivedi et al.,2011), even controlling for gender, age, medical problems, andnegative life events (Harris et al., 2006). Despite these promisingdata on the benefits for exercise in severe mental illness, little isknown about predictors of exercise within the bipolar populationand how physical activity may affect bipolar specific mood symptomsand quality of life.One recent, small study (N¼66) found that individuals withserious mental illness who preferred exercising tended to have ahigher level of education, employment rates and to be Caucasian(Sylvia et al., 2009). In the present study, we seek to replicate thesedata in bipolar disorder as well as extend these findings by examiningthe association of exercise and course of illness. Thus, we predict thata higher frequency of exercise will be associated with individuals whoare younger, educated, married, have higher incomes, as well as havebetter course of illness and life functioning (Sylvia et al., 2009).2. Methods2.1. ProcedureThe Comparative Effectiveness of a Second Generation Antipsy-chotic Mood Stabilizer and a Classic Mood Stabilizer for BipolarDisorder (CHOICE) study (Nierenberg et al., under editorial review)was a six-month multi-site, randomized comparative effectivenesstrial. CHOICE participants were randomized to receive either que-tiapine or lithium. Regardless of treatment group, all participantsreceived adjunctive personalized treatment (APT), whereby studyphysicians prescribed additional medications at their discretion.Details of the rationale, design, and methods of CHOICE are reportedelsewhere (Nierenberg et al., under editorial review). The presentanalyses examine baseline data from the CHOICE study.2.2. ParticipantsThe study protocol was approved by the Institutional ReviewBoards of the eleven study sites and participants provided verbaland written informed consent prior to initiation of any studyprocedure. Four hundred eighty two individuals with bipolardisorder between the ages of 18 and 68 enrolled in CHOICEbetween 2011 and 2012. Limited inclusion and exclusion criteriawere designed to increase diversity and generalizability within thesample (Nierenberg et al., under editorial review). To participate,individuals had to meet DSM-IV TR criteria for bipolar I or IIdisorders as well as be at least mildly symptomatic at study entry(CGI-BPZ3).2.3. MeasuresCurrent and lifetime DSM-IV TR diagnoses were determinedusing the Extended Mini-International Neuropsychiatric Interview(Sheehan et al., 1998). Demographic information, psychiatrichistory, medical history, and reported frequency of exercise wereobtained at baseline. Participants also completed the self-reportQuality-of-Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Endicott et al., 1993). Blinded raters measured severity ofbipolar symptoms with the Clinical Global Impression Scale forBipolar Disorder (CGI-BP) (Spearing et al., 1997), as well as withthe Bipolar Inventory of Symptoms Scale (BISS) (Bowden et al.,2007; Gonzalex et al., 2008). To measure overall functioning andlife satisfaction, raters administered the LIFE-Range of ImpairedFunctioning Tool (LIFE-RIFT) (Leon et al., 2000).2.4. Statistical analysisAll statistical analyses were completed using Statistical AnalysisSoftware (SAS; version 9.2, SAS Institute, Cary, NC). We used linearregression analyses to examine associations between exercisefrequency and demographic features. Post hoc contrasts wereconducted for significant variables to determine significant pair-wise differences. Linear regressions were conducted to determineif exercise frequency was associated with the percentage of lastyear spent depressed or manic/hypomanic, depression (CGI-BPand BISS), mania (CGI-BP and BISS), life satisfaction/functioning(LIFE-RIFT), and quality of life (Q-LES-Q). These analyses wereadjusted with any demographic variable(s) associated with exer-cise. The analyses examining percentage of last year spentdepressed or manic/hypomanic were also controlled for currentmood state using the BISS. Finally, we conducted linear regressionsanalyses to examine the association of exercise frequency andnumber of psychiatric comorbidities, number of medical comor-bidities, and risk factors for cardiovascular disease (i.e., triglycer-ides, fasting plasma glucose, cholesterol, body mass index,obesity).Given the exploratory nature of this paper, no adjustment formultiple hypothesis testing was made.3. ResultsDemographics and clinical features of the total sample arereported in Table 1.Two patients did not report exercise frequency at baseline andthus, were excluded from the analysis. Forty percent of partici-pants did not report exercising even one day per week while 287participants (60.0%) reported exercising at least one day per week(M¼3.7 days/week, SD¼2.0) with a range of 1 day per week(10.1%) to 7 days per week (18.5%). Exercise frequency was notassociated with any demographic variables, except marital status(p¼.025). Individuals who were married, or living as married,exercised less than individuals who were divorced or separated (F(1)¼6.31, p¼.01) and never married (F(1)¼4.90, p¼.027). Para-meter estimates for the remaining analyses were adjusted formarital status.L.G. Sylvia et al. / Journal of Affective Disorders 151 (2013) 722–727723

controlling for current manic symptoms, or BISS mania subscalescore), such that for every increase in category choice, participantsreported exercising .28 more days per week (p¼.012). We alsofound that more frequent exercise was associated with better lifefunctioning (LIFE-RIFT) and quality of life (QLESQ overall quality oflife item) (Table 2). Similar to the association of exercise withmania, patients experiencing mixed episodes at study entry(N¼82, M¼2.7972.68) tended to exercise more frequently thanindividuals who entered the study in a major depressive episode(N¼269, M¼1.7772.12). Specifically, patients entering the studyin a major depressive episode exercised significantly less than boththose patients who entered the study in a manic or hypomanicepisode (N¼56, M¼2.9972.57) (difference between the mean-s¼ ?1.22, 95% CI: ?2.10 to ?.35, po.05) or mixed episode(difference between the means¼ ?1.03, 95% CI: ?1.78 to ?0.27,po.05). There was no significant difference between the manic/hypomanic or mixed groups.In regards to medical comorbidity, a higher frequency ofexercise was associated with lower BMI such that there was a5 point increase in BMI associated with each 0.2 days per week ofless exercise (F(1)¼7.05, p¼.008). Exercise frequency was notassociated with other cardiovascular risk factors assessed in thisstudy (p4.05). In regards to psychological comorbidity, partici-pants without any comorbid anxiety disorder (defined as nothaving Panic Disorder, Agoraphobia, Social Phobia, or GeneralizedAnxiety Disorder) reported exercising marginally more often thanthose with a comorbid anxiety disorder, although this effect didnot reach significance (Odds ratio¼.94, p¼.105).4. DiscussionThis study found that approximately 40% of participantsreported not exercising at least once per week. Being married,higher BMI, more time depressed in the past year, more depressivesymptoms, lower quality of life and life functioning were asso-ciated with less frequent weekly exercise whereas spending agreater number of days being manic in the past year, having moremanic symptoms, and being in a mixed episode were associatedwith more frequent exercise.Our findings are consistent with previous studies that foundless exercise to be associated with more depressive symptoms,poorer quality of life and functioning, and higher BMI (Carless andDouglas, 2008; Crone and Guy, 2008; De Moor et al., 2006; Meadet al., 2008; Otto et al., 2007; Palomo et al., 2008; Trivedi et al.,2011; Tsang et al., 2008; Vancamfort et al., 2011). Interestingly,individuals in a manic, hypomanic, or mixed state at study entrytended to be exercising at greater frequency than individualscurrently depressed suggesting a complex relationship betweenbipolar disorder and physical activity. This dynamic has beennoted anecdotally by Wright et al. who described exercise as a“double-edged sword” for bipolar disorder, or that exercise couldhelp them to regulate their emotions and bring structure to theirchaotic lives and illness, but it may also stimulate them withconsequent affective dysregulation (Murray et al., 2011; NIH, 2006;Wright et al., 2012). In short, more research is needed to under-stand the relationship between exercise and bipolar disorder. Wedid not find significant relationships between anxiety, medicalcomorbidity, and exercise frequency, despite strong extant find-ings that relate better exercise habits with less anxiety and fewerpsychological disorders (Stephens, 1988; Strohle et al., 2006) aswell as better cardiorespiratory fitness, weight, high-densitylipoprotein cholesterol level, and fasting insulin level (Churchet al., 2007; Cornelissen and Fagard, 2005). The null findings couldbe because participants were not asked when they began toexercise as well as information about the type or intensity of theirexercise. Limitations of this study include it being a cross-sectionalanalysis, only relying on self-report of exercise frequency, notassessing type or intensity of exercise as well as whether it wascompulsive exercise. We also did not examine whether exercisemay be associated with elevated mood due to individuals becom-ing addicted with exercise; however, preliminary evidence sug-gests that exercise may not be addictive for bipolar patients (DiNicole et al., 2010).Given the mood-specific association of exercise in bipolardisorder, further research is merited to better understand therelationship between exercise and affective states in this illness,particularly the direction of causality. Overall, the present studyillustrates that exercise regimes may not be a “one size fits all”intervention, but rather an intervention that requires personaliza-tion to meet the specific needs of bipolar patients.Role of funding sourceThe Agency for Healthcare Research and Quality′s (AHRQ) provided funding forthe design, execution, and analysis of the 11-site Bipolar CHOICE study. Thisincluded assessments, participant remuneration, biostatistics support, and studystaff salary support.Conflict of interestDr. Sylvia was a shareholder in Concordant Rater Systems and serves as aconsultant for Bracket Global, Inc and Clintara. She also receives royalties from NewHarbinger Publishers.Dr. Friedman receives grant support from Repligen, Astra-Zeneca, Roche,Takeda, Neosync. He has been a consultant for Pamlab. He receives royalties fromSpringer. He has served as an expert forensic consultant for Thomson Rhodes &Cowie P.C. and Berger and Zavesky Co. L.P.A.Dr. Kocsis has received research grants and contracts from AHRQ, NIMH, NIDA,Burroughs Wellcome Trust, Pritzker Consortium, Takeda, Forest, Astra Zeneca,Roche. He is on the speaker′s bureau at Pfizer and Merck and on the advisoryboard at Corcept.Ms. Bernstein reports no competing interests in the past three years.Dr. Brody has received salary support over the past 3 years from grants fundedby Forrest, Agency for Healthcare Quality and Research, and Pritzker neuropsychia-tric disorders research consortium.Dr. Kinrys has received research support from Astra-Zeneca, Bristol-MyersSquibb Company, Cephalon, Elan Pharmaceuticals, Eli Lilly & Company, ForestPharmaceuticals Inc., GlaxoSmithkline, Sanofi/Synthelabo, Sepracor Inc., Pfizer Inc,UCB Pharma, and Wyeth-Ayerst Laboratories. He has been an advisor or consultantfor Astra-Zeneca, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc.,GlaxoSmithkline, Janssen Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma, andWyeth-Ayerst Laboratories. Dr. Kinrys has been a speaker for Astra-Zeneca, ForestPharmaceuticals Inc., GlaxoSmithkline, Sepracor Inc., and Wyeth-Ayerst Laboratories.Dr. Kemp serves on the speakers bureau for Pfizer and AstraZeneca, is aconsultant for Bristol-Myers Squibb, Teva, Corcept, Janssen. His spouse is a minorstockholder for Sanofi and Abbott.Dr. Shelton has served as a consultant to Bristol-Myers Squibb, Cyberonics, Inc.,Elan, Corp., Eli Lilly and Company, Euthymics Bioscience, Forest Pharmaceuticals,Janssen Pharmaceutica, Medtronic, Inc., Otsuka Pharmaceuticals, Pamlab, Inc., Pfizer,Inc., Ridge Diagnostics, Takeda Pharmaceuticals. Dr. Shelton has received research grantsupport from Appian Labs, Bristol-Myers Squibb, Elan, Corp., Eli Lilly and Company,Euthymics Bioscience, Forest Pharmaceuticals, Janssen Pharmaceutica, Naurex, Inc.,Novartis Pharmaceuticals, Otsuka Pharmaceuticals, Pamlab, Inc., Repligen, Corp., RidgeDiagnostics, St. Jude Medical, Inc., Takeda Pharmaceuticals.Dr. McElroy is a consultant to or member of the scientific advisory boards ofAlkermes, Bracket, Corcept, MedAvante, Shire, Sunovian, and Teva. She is a principalor co-investigator on studies sponsored by the Agency for Healthcare Research &Quality (AHRQ), Alkermes, AstraZeneca, Cephalon, Eli Lilly and Company, Forest,Marriott Foundation, National Institute of Mental Health, Orexigen Therapeutics,Inc., Pfizer, Shire, Takeda Pharmaceutical Company Ltd., and Transcept Pharmaceu-tical, Inc. She is also an inventor on United States Patent no. 6,323,236 B2, Use ofSulfamate Derivatives for Treating Impulse Control Disorders, and along with thepatent′s assignee, University of Cincinnati, Cincinnati, Ohio, has received paymentsfrom Johnson & Johnson, which has exclusive rights under the patent.Dr. Bobo reports no competing interests in the past three years.Dr. Kamali reports no competing interests in the past three years.Dr. McInnis has received grants for research support from NIMH, the Heinz CPrechter Research Fund, and the Michigan Institute for Clinical Health Research(MICHR). MM has received consulting income from the Qatar National ResearchFoundation and Merck Pharmaceuticals.Dr. Tohen was an employee of Lilly (1997 to 2008) and has received honorariafrom or consulted for AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly,L.G. Sylvia et al. / Journal of Affective Disorders 151 (2013) 722–727725